A prodrug is a compound which scarcely shows expected efficacy by itself but, after administration into the body, is converted to a drug as an active compound by undergoing metabolism by hydrolysis, oxidation, reduction, and the like under physiological conditions to show efficacy. It aims at persistence of pharmacological actions, increase in water-solubility, reduction of side effects and toxicity, improvement of stability in vivo, improvement of taste and odor, and improvement of bioavailability by oral administration (particularly, easy absorption from gastrointestinal tract) and the like, as compared to administration of the drug itself as an active compound.
When a prodrug is designed, consideration is necessary to achieve conversion to an active compound by undergoing metabolism by hydrolysis, oxidation, reduction and the like under physiological conditions. As a typical example thereof, a method including modifying a functional group that the active compound itself has such as amino group, hydroxy group, carboxy group and the like with a particular group is known. For example, it is known that a modifying group is removed by hydrolysis and the like under physiological conditions to restore an amino group, a hydroxy group or a carboxy group in a compound wherein an amino group thereof is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated when the active compound has an amino group; a compound wherein a hydroxy group thereof is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated when the active compound has a hydroxy group; a compound wherein a carboxy group thereof is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterified, pivaloyloxymethylesterified, 1-ethoxycarbonyloxyethylesterified, phthalidylesterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified or 1-cyclohexyloxycarbonyloxyethylesterified when the active compound has a carboxy group, and the like.
A naphthofuran compound represented by the following formula (A) (hereinafter sometimes to be referred to as compound (A)) has an inhibitory action on Stat3, β-catenin, Nanog pathways and the like, particularly induces apoptosis of cancer stem cells, and is a compound expected to effectively suppress cancer recurrence or metastasis (patent documents 1-5, non-patent documents 1-4).

Since compound (A) has low solubility and is unsuitable for injection, it is developed as an oral preparation. However, since it shows low oral absorbability, administration of a high dose is necessary even when pharmaceutical studies of pulverization of bulk powder, use of solubilizing agents and the like are performed, which gives rise to concern about unexpected side effects such as disorder of digestive tract and the like. Therefore, it is desired to achieve improvement of oral absorbability, persistence of pharmacological action, and reduction of side effects and toxicity by converting to a prodrug. Furthermore, since oral administration is often difficult for cancer patients, the development of an injection is also desired. Accordingly, improvement of solubility by converting to a prodrug is desired.